INTERVIEW: PDCO's Dirk Mentzer On How To Succeed With Pediatric Research
This article was originally published in Scrip
If your company is going to file a new marketing authorization for a patented drug with the European Medicines Agency, then it will likely need to think about carrying out pediatric research, a daunting prospect for many. But help is on hand through the agency's Paediatric Committee (PDCO). Its chair, Dr Dirk Mentzer, talks to Scrip about how companies can make life easier for themselves with earlier discussions and how the committee plans to improve authorization and safety for pediatric medicines.
PDCO chair, Dr Dirk Mentzer
Research in children was long neglected by the pharmaceutical industry, until the Paediatric Regulation came into force in 2007, aimed at stimulating more R&D to respond to unmet pediatric needs. Its main thrust was to establish the PDCO and require pediatric investigation plans for new drugs. PIPs are development plans that ensure a company will conduct the necessary pediatric studies when seeking a marketing authorization in the EU. Some medicines are exempt from the requirement, for example those that are highly toxic, or which treat conditions that do not appear in children, but for all other new drugs, manufacturers have to have their PIP approved by the PDCO before they can apply for marketing authorization.
PIPs are no small matter for companies and the stakes can be high. The PDCO gives an opinion on a company's proposed PIP, and as Mentzer explains, that opinion is essentially a contract between the applicant and the agency ensuring that the firm will conduct the required research in pediatric patients before it applies for marketing authorization. Failure to meet those obligations means the applicant may not receive authorization for adult populations. The ramifications are therefore big for companies, their portfolios and their finances. But if companies get it right, they could gain a six-month extension of their supplementary protection certificate (SPC), which could be financially very advantageous.
Despite the potential rewards, many companies see the PIP as something of a headache. A PIP application must be filed when pharmacokinetic studies finish, and there is criticism that this is too early in the drug development process. Mentzer admits that seven out of ten PIPs that the committee sees are for drugs that are subsequently dropped through natural drug development attrition, and companies worry they are saddled with the plan too early.
Even so, Mentzer advises a sooner-rather-than-later approach to PIPs. "Discussions with the PDCO are not a punishment, but an opportunity", he says, advising companies to come to the committee as early as possible for discussions before they submit their PIP. A number of firms fail to do this and submit their PIP application too close to the marketing authorization deadline, leaving too little time to "fix the program," says Mentzer. The PDCO has therefore helped pilot an "early dialogue forum", which means the committee can guide companies on what it will want to see in the development program and discuss potential pitfalls before PIP obligations kick in.
But Mentzer admits that the PIP system could be improved, for example, if the committee had the power to later revise an early PIP opinion. He also suggests a "high-level development strategy" could be agreed to define measurable obligations based on evolving scientific knowledge. New approaches could be on the cards as the committee's ten-year report is due next year and Mentzer says such changes to the system could be up for discussion.
The full effect of the pediatric legislation has yet to be seen in the number of new approvals suitable for children. As Mentzer points out, this is because medicines are not developed overnight: it can take up to 20 years to bring a product to market. However, he says that two thirds of the new drugs recommended by the CHMP have a pediatric investigation plan in place, which equates to between 15 and 25 a year. What the regulations have done, says Mentzer, is drive awareness of the need for more pediatric R&D and specific approvals for children.
Yet there is still more work to do to increase pediatric research, which at the moment is still driven by the needs of adults. For some diseases, this is not too much of a problem because of similarities between the needs of the two populations, says Mentzer. But in other areas it is a problem, for example in pediatric oncology and endocrinology. "Some of those areas have very special needs that you only see in children. We need further development."
Mentzer acknowledges that pediatric research is more challenging and more costly than research in adults. Children cannot, for example, give consent, they can be more susceptible to side effects and reactions, and populations tend to be small. Some of the challenges are inherent in the population and are therefore here to stay, says Mentzer. But there are ways to work around some of the problems. There are new methodologies for extrapolating from data obtained in adults and using intelligent statistical models that could, for example, reduce the requirements for a pharmacokinetic trial to calculate dosage. Or it could be possible to extrapolate from adult efficacy data, removing the need for a full-blown pediatric efficacy trial.
He adds that there is a need to examine how research led by pediatric needs is and could be funded, although that is a matter for the European Commission and member states, he says. Nevertheless, there are overlooked benefits to doing more pediatric-led research that deserve recognition: "We can learn a lot from the etiology and pathology in children that could be useful for adults. For example, although some of the pathologies in neonates are quite specific to this population, the research could yield results that help us understand other diseases in older children and adults." Mentzer also believes more needs to be done to stimulate incentives for researching off-patent medicines in children. This issue too is to be raised in the committee's ten-year report.
One thing the committee has done to encourage R&D is to amend its list of class waivers – i.e., those disease classes where a PIP is not required. These are largely based on whether the condition occurs in pediatric populations, or if the drugs are likely to be toxic in children. Last year the list was updated after a scientific review of new information showing that certain conditions do in fact affect pediatric populations. As a result eight class waivers were revoked, including liver and intrahepatic bile duct carcinoma; kidney and renal pelvis carcinoma; Parkinson's disease; and Huntington's chorea. Another nine waivers were confirmed to remain on the list, including treatments for osteoarthritis, erectile dysfunction and Alzheimer's disease.
Mentzer hopes the new class waiver list will mean PDCO will review more medicines. The committee has claimed that the previous list led to "insufficient opportunities" to consider the potential benefits of some new medicines for children. For example, between 2012 and 2014, out of 26 new anticancer medicines that were authorized for use in adults, only 14 had a development plan for use in children. There has also been concern that companies have exploited the waiver list to avoid undertaking pediatric research, but Mentzer disagrees that this happens in practice. "That is why the PDCO is there. If a company tries to elude pediatric development by requesting a waiver and the PDCO has a different opinion, then we reject the waiver. This means the company has to come up with a PIP and we have to discuss the development." There are also product-specific waivers. Around two thirds of the products that go through the CHMP for central authorization have a PIP in place, says Mentzer
Now the committee is turning its attention to post-marketing activities. Mentzer is keen to see improved pharmacovigilance of medicines used by children, and the PDCO will support the EMA's newest committee, the PRAC (Pharmacovigilance Risk Assessment Committee). He hopes the committees will combine their expertise to come up with a pilot program for surveillance and risk management that are optimal for pediatric populations. "We won't be able to answer a lot of questions about a drug until after it has been authorized. What we are trying to do with the PRAC is find the best way to perform post-marketing safety studies specific for pediatrics or specific registry requirements that can meet the needs of the children and the pediatric disease."
Working closely with the agency's other committees is not new to the PDCO, which has already entrenched itself as part of the EMA's medicines evaluations team, says Mentzer. In fact, this is one of its greatest achievements, he says. He points to the committee's work with the Committee for Orphan Medicinal Products, noting that some 50% of orphan designations are for pediatric conditions.